Matrix control of transforming growth factor-β function

Abstract

The cytokine transforming growth factor-beta (TGF-β) has multiple effects in both physiological and pathological conditions. TGF-β is secreted as part of a tripartite complex from which it must be released in order to bind to its receptor. Sequestration of latent TGF-β in the extracellular matrix (ECM) is crucial for proper mobilization of the latent cytokine and its activation. However, contrary to expectation, loss-of-function mutations in genes encoding certain matrix proteins that bind TGF-β yield elevated, rather than decreased, TGF-β levels, posing a 'TGF-β paradox.' In this review, we discuss recent findings concerning the relationship of TGF-β, ECM molecules, and latent TGF-β activation and propose a model to resolve the 'TGF-β paradox.'

Fig. 1

TGF-β latency, activation and signal transduction. Pro TGF-β forms a homodimer after synthesis and binds to LTBP via disulfide bonds, followed by a cleavage from LAP by furin proteases. LAP remains associated with mature TGF-β and forms SLC and LLC, conferring latency. Mature TGF-β is shown as a circle after LAP cleavage. After secretion, LLCs are incorporated into ECM, as LTBPs interact with FBNs. Proteolytic degradation of LAP or mechanical stretching by cell-surface integrins releases active TGF-β molecules that bind to their receptors. Active TGF-β is represented as with a blue halo. Cells respond to TGF-β through the canonical Smad-dependent pathway and non-canonical pathways, in which the mitogen-activated protein kinase (MAPK) pathways and the activation of RhoA are involved. Activated phosphoSmads form a ternary complex and, together with co-factors, induce transcription of TGF-β-responsive genes. Non-canonical pathways also influence gene expressions, and the activation of Rho kinases induces the polymerization of actin fibres. ER, endoplasmic reticulum; SRE, Smad response element.

Fig. 2

Models of the interaction between cells and defective ECM. (A) The conventional model, in which LLCs are sequestered into matrices and protected from activators. Once damage occurs to the ECM, LLCs are exposed and active TGF-β molecules are released. (B) An alternative model, which does not require ready-to-use latent TGF-β activators in the normal state. When the ECM is damaged, surrounding cells detect the alteration through cell-surface integrins, and initiate repair responses producing ECM constituents, SLCs, LLCs, together with their activators.